4 research outputs found
Optimal 10-aminoartemisinins with potent transmission-blocking capabilities for new artemisinin combination therapies–activities against blood stage P. falciparum including PfKI3 C580Y mutants and liver stage P. berghei parasites
We have demonstrated previously that amino-artemisinins including artemiside and
artemisone in which an amino group replaces the oxygen-bearing substituents attached
to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether
and artesunate, display potent activities in vitro against the asexual blood stages
of Plasmodium falciparum (Pf ). In particular, the compounds are active against late
blood stage Pf gametocytes, and are strongly synergistic in combination with the
redox active drug methylene blue. In order to fortify the eventual selection of optimum
amino-artemisinins for development into new triple combination therapies also active
against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins
based on the easily accessible and inexpensive DHA-piperazine. The latter was
converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were
screened together with the comparator drugs DHA and the hitherto most active
amino-artemisinins artemiside and artemisone against asexual and sexual blood stages
of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins
bearing aryl-urea and -amide groups are potently active against both asexual, and
late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to
those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more
active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early
results indicate these compounds tend not to display reduced susceptibility against
parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside
and artemisone will enable the development of new combination therapies that by virtue
of the amino-artemisinin component itself will possess intrinsic transmission-blocking
capabilities and may be effective against artemisinin resistant falciparum malaria.Supplementary Table 1 | In vitro activities of selected amino-artemisinins against
liver stage P. berghei, dose response curves and cytotoxicities.Supplementary Material comprises experimental details for
synthesis and characterization data of the amino-artemisinins,
and dose response curves for the in vitro P. berghei sporozoite
stage efficacy assays recorded in Excel format in CDD Vault:
UCSD CDD_Vault_Export_RESULTS_KDE_03-25-2019.This work was funded by the South African Medical Research
Council (MRC) Flagship Project MALTB-Redox with funds
from National Treasury under its Economic Competitiveness
and Support Package to RH (MRC-RFA-UFSP-01-2013), the
South African MRC Strategic Health Innovation Partnership
(SHIP) grant, a South African MRC Collaborative Center
for Malaria Research grant and South African National
Research Foundation grants (UID 84627) to L-MB and to
RH (UIDs 90682 and 98934). EW was supported by grants
from the NIH (R01 AI090141-02), and Medicines for Malaria
Venture, Geneva.http://www.frontiersin.org/Chemistryam2020BiochemistryGeneticsMicrobiology and Plant Patholog
Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1
Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(
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A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.
Radical cure of Plasmodium vivax malaria must include elimination of quiescent "hypnozoite" forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials